Background

Ovarian Cancer (OC) is the leading cause of death among gynecologic cancers in the United States.

The current standard chemotherapeutic regimen for newly diagnosed OC is a combination of a platinum-based agent with a taxane given intravenously (IV). Treatment is primarily limited by myelotoxicity.

The rationale for peritoneal administration of chemotherapy is that it directly treats the peritoneum, which is the primary site of tumor spread, and thereby may decrease systemic toxicity.

Two previous studies have addressed intraperitoneal (IP) versus IV chemotherapy, however they used different regiments and had conflicting results regarding overall survival (OS).

The Gynecology Oncology Group (GOG) therefore initiated a phase III, randomized clinical trial to study patients with OC treated with either IV paclitaxel followed by IV cisplatin or IV paclitaxel followed by IP cisplatin then IP paclitaxel.

Methods

Between March 1998 to January 2001, 429 patients were randomized for this study, of which 415 were eligible. Criteria for patient eligibility included:

Patients with stage III epithelial ovarian or peritoneal carcinoma with no residual disease greater than 1.0 cm after surgery.

Patients with a GOG performance status of 0 to 2.

0=fully active, 4= completely disabled

Patients could not have had previous chemotherapy or radiation.

The primary end points were OS and progression free survival (PFS).

The study was not strictly blinded but pathological, surgical, and eligibility information was collected prior to registration.

All surgical and pathologic eligibility information was centrally reviewed.

At the time of registration patients decided whether to have a second look laparotomy after completion of chemotherapy to check pathological response.

Second look laparotomy was performed within 8 weeks of last cycle of chemotherapy and no later than 29 weeks after study entry.

Quality of life was evaluated using the Functional Assessment of Cancer Therapy (FACT-O) at registration, before cycle four of chemotherapy, 3-6 weeks after cycle six of chemotherapy and 12 months after the completion of chemotherapy.

220 patients randomized to IV therapy, five found to be ineligible.

Day 1: Patients treated with IV paclitaxel, 135 mg per square meter of body surface area (BSA) over 24 hours.

Patient had to have absolute neutrophil count ≥1500 per cubic millimeter, platelet ≥100,000 per cubic millimeter, creatinine ≤ 2.0 mg per deciliter, and no grade 3-4 neuropathy to proceed to the next cycle of chemotherapy. In the IP group, dose was reduced for grade 2 abdominal pain. If there was persistent abdominal pain, worsening to grade 3, grade 2 neuropathy, or catheter complications, the patient was switched to IV chemotherapy.

In the event that patients did not meet these criteria, treatment was adjusted as follows: cycle delay, dose reduction, treatment with granulocyte colony stimulating factor.

If therapy was delayed more than 3 weeks the patient was dropped from the study.

In either group, in the event cisplatin had to be discontinued due to toxic effects, the patient was switched to IV carboplatin.

Results

Median follow-up: 48.2 and 52.6 months for the IV and IP groups, respectively.

Significant improvement in DFS and OS seen with IP chemotherapy compared with IV chemotherapy.

72 of 102 patients in the IV group who elected to have laparotomy, underwent the procedure. Complete PR seen in 41% of patients.

69 of 100 patients in the IP group who elected to have laparotomy, underwent the procedure. Complete PR seen in 57% of patients.

Discussion

Contrary to the belief that IP therapy would be less toxic than IV therapy, IP proved to be significantly more toxic.

May have been due to the higher cisplatin dose used in the IP group.

May be secondary to IP paclitaxel which persists in the peritoneum for one week after administration.

A significant amount of toxicity in the IP treatment group was associated with the IP catheter.

Specifying the type of catheter and the timing of placement, which was not specified in the protocol for this study, may decrease toxicity.

Use of single lumen venous catheter with a subcutaneous port for access may be superior to the fenestrated IP catheters.

Patients with left colonic/rectosigmoid resections were less likely to receive all doses of IP therapy.

It may be possible to reduce toxicity through modification of the dose, administration schedule, and type of chemotherapeutic used, however these could all affect the efficacy of the treatment and would require further clinical trials.

Authors' Conclusions

Though fewer than 50% of IP patients completed six cycles of treatment, there was a 25% reduction in risk of death with IP chemotherapy, along with the longest median survival seen in any of the phase III GOG trials (65.6 months).

This study was not designed to study the effects of the duration of IP therapy and retrospective analysis of this may introduce bias. It is therefore not possible to determine if the benefit seen with IP therapy occurs early in treatment, or if completion of the full course of therapy could be of greater benefit.

This study demonstrated a PFS and OS advantage to IP chemotherapy in Stage III OC that has been optimally resected. Though this advantage comes with increased toxicity and reduced QOL during treatment, it appears that QOL is the same after one year. The results are encouraging for the use of IP therapy in OC.